Bookmaker Consensus and Agreement for the UEFA Champions League 2008/09

Bookmakers odds are an easily available source of ``prospective" information that is thus often employed for forecasting the outcome of sports events. To investigate the statistical properties of bookmakers odds from a variety of bookmakers for a number of different potential outcomes of a sports event, a class of mixed-effects models is explored, providing information about both consensus and (dis)agreement across bookmakers. In an empirical study for the UEFA Champions League, the most prestigious football club competition in Europe, model selection yields a simple and intuitive model with team-specific means for capturing consensus and team-specific standard deviations reflecting agreement across bookmakers. The resulting consensus forecast performs well in practice, exhibiting high correlation with the actual tournament outcome. Furthermore, the teams' agreement can be shown to be strongly correlated with the predicted consensus and can thus be incorporated in a more parsimonious model for agreement while preserving the same consensus fit.Series: Research Report Series / Department of Statistics and Mathematic

APPLICATION OF PHARMACOMETRIC METHODS TO OPTIMIZE TRIAL DESIGN AND DOSING IN CRITICALLY ILL INFANTS

Christoph P. Hornik: Application of Pharmacometric Methods to Optimize Trial Design and Dosing in Critically Ill Infants (under the direction of Daniel Gonzalez) Drug development in critically ill infants is challenging. Limited number of eligible trial participants, low consent rates, inability to perform or tolerate trial assessments, and ethical considerations all contribute to a low rate of successful clinical trials in this population. As a result, drugs administered to infants are often incompletely studied to ensure their efficacy and safety, and administered without a US Food and Drug Administration (FDA)-approved indication (off-label). Off-label drug use is associated with increased risk of unwanted drug toxicities or therapeutic failures, which can result in poor infant outcomes. To improve infant outcomes, innovative strategies in drug development are needed to generate the data necessary to identify safe and effective drug dosing regimens. The work performed in this dissertation provides 3 examples of innovative approaches to drug development in critically ill infants. Central to these innovations is leveraging pharmacometric methods to address 3 common obstacles: (1) sample size determination of infant pharmacokinetic (PK) trials; (2) characterization of the relationship between drug exposure and efficacy to identify efficacious doses; and (3) evaluation of the association between drug exposure and safety to identify safe doses. Each of these 3 obstacles is overcome with the help of a specific pharmacometric approach. In aim 1, populationPK (popPK) modeling and simulation is applied to determine optimal sample sizes for various infant PK trial designs. In aim 2, popPK/pharmacodynamic (PD) modeling is used to characterize the exposure response relationship between methylprednisolone and antiinflammatory changes in neonates undergoing cardiac surgery on cardiopulmonary bypass (CPB). In aim 3, popPK models are combined with electronic health record (EHR)-derived real-world data (RWD) sources to develop a novel platform to study the relationship between predicted drug exposures and safety events captured during routine clinical care.Doctor of Philosoph

Clinical Pharmacology Studies in Critically Ill Children

Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs

Risk Factors and In-Hospital Outcomes following Tracheostomy in Infants

To describe the epidemiology, risk factors, and in-hospital outcomes of tracheostomy in infants in the neonatal intensive care unit (NICU)

Tracheostomy after Surgery for Congenital Heart Disease: An Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database

Background Information concerning tracheostomy after operations for congenital heart disease has come primarily from single-center reports. We aimed to describe the epidemiology and outcomes associated with postoperative tracheostomy in a multi-institutional registry. Methods The Society of Thoracic Surgeons Congenital Heart Database (2000 to 2014) was queried for all index operations with the adverse event “postoperative tracheostomy” or “respiratory failure, requiring tracheostomy.” Patients with preoperative tracheostomy or weighing less than 2.5 kg undergoing isolated closure of patent ductus arteriosus were excluded. Trends in tracheostomy incidence over time from January 2000 to June 2014 were analyzed with a Cochran-Armitage test. The patient characteristics associated with operative mortality were analyzed for January 2010 to June 2014, including deaths occurring up to 6 months after transfer of patients to long-term care facilities. Results From 2000 to 2014, the incidence of tracheostomy after operations for congenital heart disease increased from 0.11% in 2000 to a high of 0.76% in 2012 (p < 0.0001). From 2010 to 2014, 648 patients underwent tracheostomy. The median age at operation was 2.5 months (25th, 75th percentile: 0.4, 7). Prematurity (n = 165, 26%), genetic abnormalities (n = 298, 46%), and preoperative mechanical ventilation (n = 275, 43%) were common. Postoperative adverse events were also common, including cardiac arrest (n = 131, 20%), extracorporeal support (n = 87, 13%), phrenic or laryngeal nerve injury (n = 114, 18%), and neurologic deficit (n = 51, 8%). The operative mortality was 25% (n = 153). Conclusions Tracheostomy as an adverse event of operations for congenital heart disease remains rare but has been increasingly used over the past 15 years. This trend and the considerable mortality risk among patients requiring postoperative tracheostomy support the need for further research in this complex population

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK)

Sedation, Analgesia, and Paralysis during Mechanical Ventilation of Premature Infants

To characterize administration of sedatives, analgesics, and paralytics in a large cohort of mechanically ventilated, premature infants

Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants

Abstract Background The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood. Objectives The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants. Methods We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model. Results We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC 24,SS ) and maximum concentration of sildenafil (C max,SS,SIL ) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC 24,SS ; 1.19 (0.78, 1.82) for C max,SS,SIL . Conclusions We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted

Medication Use in the Neonatal Intensive Care Unit

We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time